Purpose: We have shown that the phenotypically undifferentiated (PSA−/lo) prostate cancer cell population harbors long-term self-renewing cancer stem cells (CSC) that resist castration, and a subset of the cells within the PSA−/lo population bearing the ALDHhiCD44+α2β1+ phenotype (Triple Marker+/TM+) is capable of robustly initiating xenograft tumors in castrated mice. The goal of the current project is to further characterize the biologic properties of TM+ prostate cancer cell population, particularly in the context of initiating and propagating castration-resistant prostate cancer (CRPC).
Experimental Design: The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent and androgen-independent prostate cancer xenograft models. In vitro clonal, clonogenic, and sphere-formation assays were conducted in cells purified from xenograft and patient tumors. qPCR, Western blot, lentiviral-mediated gene knockdown, and human microRNA arrays were performed for mechanistic studies.
Results: By focusing on the LAPC9 model, we show that the TM+ cells are CSCs with both tumor-initiating and tumor-propagating abilities for CRPC. Moreover, primary patient samples have TM+ cells, which possess CSC activities in “castrated” culture conditions. Mechanistically, we find that (i) the phenotypic markers are causally involved in CRPC development; (ii) the TM+ cells preferentially express castration resistance and stem cell–associated molecules that regulate their CSC characteristics; and (iii) the TM+ cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir.
Conclusions: Our results define the TM+ prostate cancer cells as a population of preexistent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM+ cell population as a therapeutic target. Clin Cancer Res; 22(17); 4505–16. ©2016 AACR.
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
- Received December 10, 2015.
- Revision received March 15, 2016.
- Accepted March 27, 2016.
- ©2016 American Association for Cancer Research.